Exploring CD38 molecular biology and imaging in multiple myeloma pathogenesis

探索多发性骨髓瘤发病机制中的 CD38 分子生物学和影像学

• 批准号: 10405639
• 负责人: Monica Shokeen
• 金额: $ 61.09万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405639
• 关键词: Address; Affinity; African ancestry; Age; Antibodies; Antibody Therapy; Antigens; Benchmarking; Binding; Biological; Bone marrow biopsy; Cells; Cessation of life; Clinic; Clinical; Data; Diagnostic tests; Disease remission; Enzymes; Epitopes; Family history of; Foxes; Generations; Goals; Green Fluorescent Proteins; Half-Life; Hematologic Neoplasms; Human; Image; Imaging Device; Immune; Immunotherapy; Integral Membrane Protein; Knowledge; Lead; Link; Luciferases; Malignant lymphoid neoplasm; Metabolism; Modeling; Molecular; Molecular Biology; Molecular Conformation; Monitor; Monoclonal Antibodies; Multiple Myeloma; Mus; Nicotinamide adenine dinucleotide; Order Coleoptera; Organ; Pathogenesis; Pathway interactions; Patients; Peptides; Phage Display; Phenotype; Positron-Emission Tomography; Proteins; Radiolabeled; Radiopharmaceuticals; Recurrent disease; Refractory; Refractory Disease; Relapse; Resistance; Risk Factors; SCID Mice; Sampling Errors; Signaling Molecule; Spatial Distribution; Technology; Testing; Therapeutic Uses; Therapeutic antibodies; Tracer; Tumor Tissue; Universities; Virginia; age related; base; biological systems; extracellular; fluorodeoxyglucose; human model; human old age (65+); imaging agent; imaging probe; imaging study; in vivo; innovation; male; molecular imaging; mouse model; neoplastic cell; novel; patient variability; protein aminoacid sequence; quantitative imaging; receptor; receptor expression; response; serial imaging; sex; small molecule; spatial relationship; spatiotemporal; standard of care; subcutaneous; targeted treatment; treatment response; tumor; uptake

Multiple myeloma (MM) is the 2nd most common, age related, hematological malignancy with an estimated 30,000 new cases and 13,000 deaths per year. Patients with upfront refractory disease progress fast, and those that enter remission eventually die as a consequence of relapsed disease. To increase patient survival, clinicians need new ways of selecting effective and durable therapies for relapsed and refractory MM patients. Antibody (Ab) based treatments that target cluster of differentiation 38 (CD38), a transmembrane protein consistently expressed in MM cells, is a promising therapy for relapsed and refractory MM patients. Currently, there are three CD38 targeted monoclonal Abs (mAbs) in the clinic for MM patients, daratumumab, isatuximab and MOR-202. These Abs are safe, well tolerated and show remarkable efficacy in ~30% of myeloma patients. It is unknown why the majority of remaining patients do not respond to CD38 targeted mAb therapy and why there is such variability between patients. Functionally, CD38 is a pleiotropic antigen that acts as an enzyme as well as a receptor. The extracellular enzymatic component of CD38 is responsible for the metabolism of nicotinamide adenine dinucleotide (NAD) to downstream Ca2+ signaling molecules. There is growing evidence that variability in CD38 targeted therapy response in MM cells could in large part be contributed to the changes in its NAD enzymatic activity. Here, we posit that while CD38 expression is important, the monitoring of CD38 enzymatic activity in concert with spatiotemporal imaging is key to linking MM response to CD38 targeted therapies. We propose to address this question using Positron Emission Tomography (PET), which is a powerful molecular imaging tool that can be directly applied to quantify receptor expression and functional activity in vivo, non- destructively and longitudinally. We have shown that PET imaging of CD38 antigen on MM cells is feasible using the radiolabeled CD38 mAb daratumumab. A limitation of this approach however is that Abs are not suited for longitudinal imaging studies due to their long biological half-life. High-affinity peptide based small molecule imaging agents can effectively overcome these limitations since they are rapidly taken up by tumor tissue while being promptly cleared from non-target organs in vivo. Despite the unmet need, there is a paucity of CD38 targeted small molecule peptide based PET probes for MM. Using innovative phage display technology, we will develop new CD38 targeted peptide-based PET imaging probes that are specific for enzymatically activate CD38 conformation. Furthermore, in highly relevant biological systems, we will evaluate molecular pathways as well as spatial relationships that govern MM-associated CD38 expression. The specific aims are: (1) Aim 1a. Identify and validate changes in CD38 expression and enzymatic activity before and after CD38 targeted therapies in human mouse models of MM. Aim 1b. Evaluate spatiotemporal CD38 expression based on PET imaging. (2) Aim 2. Develop, evaluate and optimize novel high affinity CD38 targeted peptide PET probes. In summary, the current proposal is innovative and potentially clinically transformative since it seeks to identify those MM patients who are most sensitive and most resistant to anti-CD38 monoclonal immunotherapy.

多发性骨髓瘤(MM)是第二种最常见的与年龄相关的血液系统恶性肿瘤，据估计 每年新增30,000例，死亡13,000人。患有早期难治性疾病的患者进展很快，而那些 进入缓解期的人最终会死于复发的疾病。为了提高患者的存活率，临床医生 需要新的方法为复发和难治性多发性骨髓瘤患者选择有效和持久的治疗方法。抗体 (AB)以分化簇38(CD38)为靶点的治疗，CD38是一种一贯的跨膜蛋白 在MM细胞中表达，是治疗复发和难治性MM患者的一种有前途的治疗方法。目前，有三家 CD38靶向单抗(MAbs)在临床上用于MM患者，达拉图单抗、伊沙妥昔单抗和MOR-202。 这些抗体是安全的，耐受性好，在约30%的骨髓瘤患者中显示出显著的疗效。这是未知的 为什么大多数剩下的患者对CD38靶向单抗治疗没有反应，为什么有这样的反应 患者之间的可变性。从功能上讲，CD38是一种多效性抗原，既可以作为一种酶，也可以作为一种 受体。CD38的胞外酶成分负责烟酰胺的代谢 腺嘌呤二核苷酸(NAD)到下游的钙信号分子。越来越多的证据表明，变异性 在CD38中，MM细胞的靶向治疗反应在很大程度上可能与其NAD的变化有关 酶活性。在这里，我们假设虽然CD38的表达很重要，但对CD38酶的监测 结合时空成像的活动是将多发性骨髓瘤的反应与CD38靶向治疗联系起来的关键。我们 建议使用正电子发射断层扫描(PET)来解决这个问题，正电子发射断层扫描是一种强大的分子 可直接用于定量体内受体表达和功能活性的成像工具，非 破坏性的和纵向的。我们已经证明，在MM细胞上进行CD38抗原的PET成像是可行的 放射性标记的CD38单抗Daratumumab。然而，这种方法的局限性是，抗体不适合于 由于它们的生物半衰期很长，所以纵向成像研究。基于高亲和力多肽的小分子 显像剂可以有效地克服这些限制，因为它们在被肿瘤组织迅速吸收的同时 被迅速清除出体内的非靶器官。尽管需求未得到满足，但CD38仍然匮乏 针对MM的靶向小分子多肽PET探针。利用创新的噬菌体展示技术，我们将 开发新型针对CD38的多肽PET成像探针，用于酶激活CD38 构象。此外，在高度相关的生物系统中，我们也将评估分子途径。 作为支配MM相关CD38表达的空间关系。具体目标是：(1)目标1a。识别 并验证CD38靶向治疗前后CD38表达和酶活性的变化 目的：建立MM的人-鼠模型。基于PET成像评价CD38的时空表达。(2) 目的2.研制、评价和优化新型高亲和力CD38靶向多肽PET探针。 总而言之，目前的建议是创新的，并可能在临床上产生变革，因为它试图确定 对抗CD38单抗免疫治疗最敏感和最耐药的MM患者。